7204 - Clinical Diagnosis of Acute Porphyria

Brief Summary

Primary Objectives:

a. To determine the prevalence of abnormal lab tests and porphyria-like symptoms in adult family members of an index case of acute porphyria – Acute Intermittent Porphyria (AIP), Hereditary Copropophyria (HCP), and Variegate Porphyria (VP) - who are confirmed heterozygotes of the proband's genetic defect; based on these data, to devise a clinical index for the likelihood of the being heterozygous for an acute porphyria mutation.

b. To test the utility of the index prospectively in patients with a possible diagnosis of acute porphyria based on elevated urinary porphyrins or porphyrin precursors and the major features of the index. A control group will consist of sex- and age matched individuals who are not selected by symptoms but have elevated urinary porphyrins or porphyrin precursors.

Secondary Objective:

To assess the frequency of disease manifestations in genetically confirmed AIP, HCP and VP; to assess the prevalence of acute porphyria in a population with elevation of urine proporphyrins and pain symptoms.

Detailed Description

All types of porphyria represent disturbances in the formation of heme, an essential component of hemoglobin and cellular cytochromes. Each is due to a hereditary or acquired defect in one of the enzymes of heme synthesis. The enzyme defect restricts the flow of heme precursors, with spillover of intermediates to excretory routes. The porphyrias are divided into acute (neurologic) and chronic (cutaneous) forms. In the acute form, neuropathic symptoms predominate, including ileus, visceral pain, seizures, motor neuron disease and (when advanced) respiratory paralysis. Many genetic carriers have no symptoms. Attacks are induced classically by medications that increase the demand for heme production. In the cutaneous types, porphyrins accumulate in the skin causing photosensitivity.
Hereditary coproporphyria (HCP) involves a mutation in coproporphyrinogen oxidase, which catalyzes the conversion of coproporphyinogen to protoporphyrinogen. People with active HCP display features of both acute and cutaneous porphyria; photosensitivity may occure in the absence of acute symptoms in some individuals. HCP appears to be expressed clinically less frequently than is acute intermittent porphyria. Its prevalence in the American population is unknown, but i may be relatively common. In asymptomatic individuals, urinary and fecal coproporphyrin generally are mildly elevated, although it is unclear if all genetic carriers exhibit even these markers. The biochemical evaluation is complicated by the fact that excess urinary coproporphyrin occurs also in a large number of health conditions unrelated to porphyria -- most commonly liver disease, but also neurological and hematological conditions (13). This is a major cause of confusion for patients and leads to much misdiagnosis.

Contact Information

The clinical and biochemical signs of acute porphyria appear only after puberty. Therefore the study participants in all groups will be adults, although participants age 15-17 may be considered, with parental consent.

All research subjects must be capable of understanding, and in agreement with, the purposes of the study, which will include genetic testing.

Group 1:

First-degree relative of an individual with a disease-causing mutation in either the HMBS, CPOX, or PPOX gene, who has never had genetic testing.

At least a 2-fold increase in any porphyria screening test (i.e. total urinary porphyrins, plasma porphyrins, fecal porphyrins, etc) relative to the ULN for the testing lab, performed within two years of screening date.